- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
To permit adequate absorption of alendronate:Alendronic Acid 70mg Tablets must be taken at least 30 minutes before the first food, beverage or medicinal product of the day with plain water only. Other beverages (including mineral water), food and some medicinal products are likely to reduce the absorption of alendronate (see section 4.5).To facilitate delivery to the stomach and thus reduce the potential for local and oesophageal irritation/adverse experiences (see section 4.4):• Alendronic Acid 70mg Tablets should only be swallowed upon arising for the day with a full glass of water (not less than 200 ml or 7 fl.oz.). • Patients should only swallow Alendronic Acid 70mg Tablets whole. Patients should not crush or chew the tablet or allow the tablet to dissolve in their mouths because of a potential for oropharyngeal ulceration.• Patients should not lie down until after their first food of the day which should be at least 30 minutes after taking the tablet.• Patients should not lie down for at least 30 minutes after taking Alendronic Acid 70mg Tablets.• Alendronic Acid 70mg Tablets should not be taken at bedtime or before arising for the day.Patients should receive supplemental calcium and vitamin D if dietary intake is inadequate (see section 4.4).Use in the elderly: In clinical studies there was no age-related difference in the efficacy or safety profiles of alendronate. Therefore no dosage adjustment is necessary for the elderly.Use in renal impairment: No dosage adjustment is necessary for patients with GFR greater than 35 ml/min. Alendronate is not recommended for patients with renal impairment where GFR is less than 35 ml/min, due to lack of experience.Paediatric population: Alendronate sodium is not recommended for use in children under the age of 18 years due to insufficient data on safety and efficacy in conditions associated with paediatric osteoporosis (also see section 5.1).Alendronic Acid 70mg Tablets has not been investigated in the treatment of glucocorticoid-induced osteoporosis.
PregnancyAlendronate should not be used during pregnancy. There are no adequate data from the use of alendronate in pregnant women. Animal studies do not indicate direct harmful effects with respect to pregnancy, embryonal/fetal development, or postnatal development. Alendronate given during pregnancy in rats caused dystocia related to hypocalcemia (see section 5.3).
BreastfeedingIt is not known whether alendronate is excreted into human breast milk. Alendronate should not be used by breast-feeding women.
|One-Year Study||Three-Year Studies|
|Alendronate Once Weekly 70 mg (n=519) %||alendronate 10 mg/day (n=370) %||alendronate 10 mg/day (n=196) %||Placebo (n=397) %|
|musculoskeletal (bone, muscle or joint) pain||2.9||3.2||4.1||2.5|
Immune system disorders:Rare: hypersensitivity reactions including urticaria and angioedema
Metabolism and nutrition disorders:Rare: symptomatic hypocalcaemia, often in association with predisposing conditions §
Nervous system disorders:Common: headache, dizzinessUncommon: dysgeusia
Eye disorders:Uncommon: eye inflammation (uveitis, scleritis, episcleritis)
Ear and labyrinth disorders:Common: vertigo
Gastrointestinal disorders:Common: abdominal pain, dyspepsia, constipation, diarrhoea, flatulence, oesophageal ulcer*, dysphagia*, abdominal distension, acid regurgitationUncommon: nausea, vomiting, gastritis, oesophagitis*, oesophageal erosions*, melenaRare: oesophageal stricture*, oropharyngeal ulceration*, upper gastrointestinal PUBs (perforation, ulcers, bleeding) §
Skin and subcutaneous tissue disorders:Common: alopecia, pruritusUncommon: rash, erythemaRare: rash with photosensitivity, severe skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis
Musculoskeletal, connective tissue and bone disorders:Very common: musculoskeletal (bone, muscle or joint) pain which is sometimes severe§Common: joint swellingRare: Osteonecrosis of the jaw §, subtrochanteric and diaphyseal femoral fractures (bisphosphonate class adverse reaction) #Very rare: Osteonecrosis of the external auditory canal (bisphosphonate class adverse reaction).
General disorders and administration site conditions:Common: asthenia, peripheral oedemaUncommon: transient symptoms as in an acute-phase response (myalgia, malaise and rarely, fever), typically in association with initiation of treatment.§. See section 4.4. Frequency in Clinical Trials was similar in the drug and placebo group.
* See sections 4.2 and 4.4.This adverse reaction was identified through post-marketing surveillance. The frequency of rare was estimated based on relevant clinical trials#. Identified in postmarketing experience.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Treatment of post-menopausal osteoporosisOsteoporosis is defined as bone mineral density (BMD) of the spine or hip 2.5 standard deviations below the mean value of a normal young population or as a previous fragility fracture, irrespective of bone mineral density.The therapeutic equivalence of alendronate once-weekly tablets (n=519) and alendronate 10 mg daily (n=370) was demonstrated in a one-year multicentre study in post-menopausal women with osteoporosis. The mean increase from baseline of BMD in the lumbar spine after one year was 5.1 % (95 % confidence interval: 4.8, 5.4 %) in the group receiving 70 mg once per week and 5.4 % (95 % confidence interval: 5.0, 5.8 %) in the group receiving 10 mg daily. The average increases in BMD in the group receiving 70 mg once per week and in the group receiving 10 mg daily were 2.3 % and 2.9 % in the femoral neck and 2.9 % and 3.1 % over the total hip. The two treatment groups were also similar with regard to increased bone density in other parts of the skeleton.The effects of alendronate on BMD and fracture incidence in post-menopausal women were studied in two initial efficacy studies of identical design (n=994), and in the Fracture Intervention Trial (FIT: n=6459).In the initial efficacy studies, the increases in BMD with alendronate 10 mg daily relative to placebo after three years were 8.8 %, 5.9 % and 7.8 % at the spine, femoral neck and trochanter respectively. Total body BMD also increased significantly. In the patients treated with alendronate, the proportion of patients who suffered one or more vertebral fractures was reduced by 48 % (alendronate 3.2 % versus placebo 6.2 %). In the two-year extensions of these studies the BMD in the spine and trochanter continued to increase. In addition, BMD at the femoral neck and total body was maintained.The FIT study included two placebo-controlled trials in which alendronate was given daily (5 mg daily for two years and 10 mg daily for a further one or two years).• FIT 1: A three-year study with 2027 patients who had had at least one baseline vertebral (compression) fracture. In this study alendronate daily reduced the incidence of ≥1 new vertebral fracture by 47 % (alendronate 7.9 % versus placebo 15.0 %). In addition, a statistically significant reduction in the incidence of hip fractures was confirmed (1.1 % versus 2.2 %, a reduction of 51 %).• FIT 2: A four-year study with 4432 patients who had a low bone mass but had not had any vertebral fracture at the start of the study. In this study, in a subgroup analysis of osteoporotic women (37 % of the total population who fulfilled the definition of osteoporosis given above) a significant difference was seen in the incidence of hip fractures (alendronate 1.0 % versus placebo 2.2 %, a reduction of 56 %) and in the incidence of ≥1 vertebral fracture (2.9 % versus 5.8 %, a reduction of 50 %).Paediatric patients: Alendronate sodium has been studied in a small number of patients with osteogenesis imperfecta under the age of 18 years. Results are insufficient to support the use of alendronate sodium in paediatric patients with osteogenesis imperfecta.
AbsorptionCompared with an intravenous reference dose, the mean oral bioavailability of alendronate in women was 0.64 % for doses ranging from 5 to 70 mg given after an overnight fast and two hours before a standardised breakfast. Bioavailability decreased to an estimated 0.46 % and 0.39 % when alendronate was given an hour or half an hour before a standardised breakfast.In osteoporosis studies alendronate was effective when it was given at least 30 minutes before the first meal or drink of the day. Bioavailability was negligible irrespective of whether alendronate was given together with or up to two hours after a standardised breakfast. Concomitant administration of alendronate with coffee or orange juice reduced bioavailability by approx. 60 %. In healthy persons, oral prednisolone (20 mg three times daily for five days) did not result in any clinically meaningful change in the oral bioavailability of alendronate (a mean increase ranging from 20 % to 44 %).
DistributionStudies in rats show that alendronate is initially distributed to soft tissues after intravenous administration of 1 mg/kg, but is then rapidly redistributed to the skeleton or excreted in the urine. The mean steady-state volume of distribution, exclusive of bone, is at least 28 litres in humans. Concentrations of drug in plasma following therapeutic oral doses are too low for analytical detection (<5 ng/ml). Protein binding in human plasma is approximately 78%.
BiotransformationThere is no evidence that alendronate is metabolised in animals or humans.
EliminationFollowing a single intravenous dose of (14C) alendronate, approximately 50% of the radioactivity was excreted in the urine within 72 hours and little or no radioactivity was recovered in the faeces. Following a single intravenous dose of 10 mg, the renal clearance of alendronate was 71 ml/min, and systemic clearance did not exceed 200 ml/min. Plasma concentrations fell by more than 95% within 6 hours following intravenous administration. The terminal half-life in humans is estimated to exceed ten years, reflecting release of alendronate from the skeleton. Alendronate is not excreted through the acidic or basic transport systems of the kidney in rats, and thus it is not thought to interfere with the excretion of other drugs by those systems in humans.
Characteristics in patientsPreclinical studies show that the drug that is not deposited in bone is rapidly excreted in the urine. No evidence of saturation of bone uptake was found after chronic dosing with cumulative intravenous doses up to 35 mg/kg in animals. Although no clinical information is available, it is likely that, as in animals, elimination of alendronate via the kidney will be reduced in patients with impaired renal function. Therefore, somewhat greater accumulation of alendronate in bone might be expected in patients with impaired renal function (see section 4.2).
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